Research ArticlePrevalence of Steatosis Hepatis in the Eurotransplant Region:Impact on Graft Acceptance Rates

SimonMoosburner ,1 JosephM. G. V. Gassner,1 Maximilian Nösser,1

Julian Pohl,1 David Wyrwal,1 Felix Claussen,1 Paul V. Ritschl,1,2 Duska Dragun,3

Johann Pratschke,1 Igor M. Sauer ,1 and Nathanael Raschzok 1,2

1Department of Surgery, Campus Charite Mitte | Campus Virchow-Klinikum, Experimental Surgery and Regenerative Medicine,Charite – Universitatsmedizin Berlin 13353, Germany2BIH Charite Clinician Scientist Program, Berlin Institute of Health (BIH), Berlin 10178, Germany3Berlin Institute of Health and Department of Nephrology and Critical Care Medicine, Charite Universitatsmedizin,Berlin 13353, Germany

Correspondence should be addressed to Igor M. Sauer; igor.sauer@charite.de

Received 17 July 2018; Accepted 17 October 2018; Published 1 November 2018

Academic Editor: Shu-Sen Zheng

Copyright © 2018 Simon Moosburner et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Due to the shortage of liver allografts and the rising prevalence of fatty liver disease in the general population, steatotic liver grafts areconsidered for transplantation.This condition is an important risk factor for the outcome after transplantation. We here analyze thecharacteristics of the donor pool offered to the Charite – Universitatsmedizin Berlin from 2010 to 2016 with respect to liver allograftnonacceptance and steatosis hepatis. Of the 2653 organs offered to our center, 19.9% (n=527) were accepted for transplantation,58.8% (n=1561) were allocated to other centers, and 21.3% (n = 565) were eventually discarded from transplantation. In parallelto an increase of the incidence of steatosis hepatis in the donor pool from 20% in 2010 to 30% in 2016, the acceptance rates forsteatotic organs increased in our center from 22.3% to 51.5% in 2016 (p < 0.001), with the majority (86.9%; p > 0.001) having lessthan 30% macrovesicular steatosis hepatis. However, by 2016, the number of canceled transplantations due to higher grades ofsteatosis hepatis had significantly increased from 14.7% (n = 15) to 63.6% (42; p < 0.001). The rising prevalence of steatosis hepatisin the donor pool has led to higher acceptance rates of steatotic allografts. Nonetheless, steatosis hepatis remains a predominantphenomenon in discarded organs necessitating future concepts such as organ reconditioning to increase graft utilization.

1. Introduction

Orthotopic liver transplantation (OLT), which is the onlycurative therapy option in patients with end-stage liver dis-ease, is increasingly limited by the discrepancy between organdemand and availability [1, 2]. Donation after cardiac death,split-liver transplantation, living donor liver transplantation,and transplantation of grafts from extended criteria donorshave been developed to expand the donor pool [3, 4]. In spiteof these developments, and due to the increase in donor ageand stagnation of donations, the number of patients on thewaiting list constantly exceeds the organ supply [5].While thenumber of liver transplantations decreased, more restrictivelisting policies have led to sicker patients on the waiting list,

with high rates of mortality and impaired outcome after livertransplantation [6–8].

Steatosis hepatis, also known as fatty liver disease, isconsidered an important risk factor for graft dysfunctionafter liver transplantation, and more than 50% of grafts withhistologically confirmed moderate or severe macrosteatosisare usually not used for transplantation [9]. Nonalcoholicfatty liver disease, which is the hepatic manifestation of themetabolic syndrome, is already the second most commoncause for liver transplantation in the USA and currently theonly increasing etiology with increasing incidence [10–13].With the rising prevalence of steatosis hepatis in potentialdonors, graftutilization is expected to fall from78% to 44%by2030 [10]. However, data on the current nonacceptance rate

HindawiHPB SurgeryVolume 2018, Article ID 6094936, 9 pageshttps://doi.org/10.1155/2018/6094936

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of liver grafts due to steatosis hepatis in the Eurotransplantregion are not well documented in the literature. Basedon large retrospective database analyses, transplantation ofliver grafts with macrovesicular steatosis > 30% is onlyrecommended from donors with less overall risk factors [14,15]. Even though macrovesicular steatosis is a recognizedrisk factor for primary nonfunction and early allograftdysfunction (EAD) [14–21], the extent of the postoperativeimpairment remains disputed. It is generally accepted thatsevere macrovesicular steatosis ≥ 60% leads to higher rates ofprimary nonfunction and EAD, and to reduced 1- and 3-yearrecipient and graft survival [16, 22, 23], while mild steatoticorgans seem to be safe to transplant [14, 15, 24].

Germany in particular has seen a drastic 30% decline inorgan donation, from 1200 donors in 2011 to only 857 donorsin 2016.This aggravates the need to offer grafts fromextendedcriteria donors to meet the demand for liver allografts. Thequestion arises if expanding the donor pool with such donorshas actually yielded higher rates of transplantations or justhigher rates of notaccepted livers. To address this questionand to update the knowledge concerning liver graft utiliza-tion and reasons for nonacceptance in the Eurotransplantregion [25], we here analyzed all grafts offered to our high-volume center from 2010 to 2016 with regard to allocation,i.e., acceptance, nonacceptance, or discarded organs, with aspecial focus on grafts with steatosis hepatis.

2. Materials and Methods

2.1. Study Site and Ethical Board Approval. This singlecenter retrospective data analysis was performed in theDepartment of Surgery, Campus Charite Mitte | CampusVirchow-Klinikum of the Charite – UniversitatsmedizinBerlin (Berlin, Germany). The study protocol was approvedby the local ethics committee (Ethics committee of theCharite, EA2/010/17).

2.2. Organ Offers. Data for all livers from 2010 to 2016 offeredby Eurotransplant to the Charite – UniversitatsmedizinBerlin was requested from Eurotransplant and analyzed.All donors included in the analysis were from brain deathdonors (DBD). Donor data included in analysis weredonor age, body mass index (BMI), hepatitis B (HBV)status, hepatitis C (HCV) status, aspartate-aminotransferase(AST), alanine-aminotransferase (ALT), gamma-glutamyltransferase (GGT), international normalized ratio (INR), c-reactive protein (CRP), creatinine, sodium, history of dia-betes mellitus, or smoking, cardiopulmonary resuscitation,cause of death, duration of intensive care unit (ICU) stay,signs for steatosis hepatis in ultrasonography, steatosis hep-atis in histopathology report, and the allocation phase, i.e.,whether the offered donor liver was procured or transplantedat all.

2.3. Organ Acceptance. All liver offers made to the Charite– Universitatsmedizin Berlin are recorded and in case ofnonacceptance the reason is remarked. Clinic records werescreened from 2010 to 2016. Reason of nonacceptance was

categorized into “donor medical,” “weight/size,” “recipientmedical,” “logistics,” or “other reasons.” “Donor medical”was further subclassified into “age,” “biochemical param-eters,” “cardiopulmonary resuscitation,” “steatosis hepatis,”“infection,” “malignancy,” “substance abuse,” “ICU stay,” or“other reasons.” Liver allografts were accepted on a case-by-case basis for each individual patient, considering donorage, weight, and size relative to recipient age, as well as thevirologic status of the donor (especially HCV and humanimmunodeficiency virus). Additionally, the expected coldischemia time (CIT) and the presence of steatosis hepatisinfluenced the acceptance decision.

2.4. Classification of Steatosis Hepatis. Steatosis hepatis isclassified into two groups: (I) any description of steatosishepatis, i.e., ultrasound or histopathological report; (II) caseswith histopathological confirmation. The histopathologicalconfirmed cases were further graded by the degree ofmacrovesicular steatosis hepatis as previously reported byChu et al. and Briceno et al. [24, 26]. Macrovesicular steatosis< 5% was classified as “no steatosis,” followed by < 30% as“mild steatosis,” ≥ 30% as “moderate steatosis,” and ≥ 60%as “severe steatosis.” In addition, 1-year graft and recipientsurvival rates were calculated. Graft survival was defined asthe absence of recipient death or retransplantation. Earlyallograft dysfunction was calculated for all recipients anddefined as bilirubin ≥ 10mg/dl or INR ≥ 1.6 on POD 7 orAST/ALT >2000 IU/l during the first 7 days [17].

2.5. Statistical Analysis. Data is presented as mean± standarddeviation (SD) for normal distribution of data. Not normallydistributed data is reported in median and interquartilerange. Categorical variables were measured in proportionsand counts. After testing for normality, continuous para-metric variables were analyzed with the Student’s t-test andnonparametric variables using the Wilcoxon rank-sum test.Grouped variables were analyzed with the one-way ANOVAor the Kruskal-Wallis test according to normality. Categoricalvariables were analyzed using the Pearson 𝜒2 test.

A binary logistic regression analysis for liver acceptancewas carried out. Age was classified into groups of <50 yearsand above 50 into decades: 50-59, 60-69, 70-79, and >80.BMI was classified in a similar way: < 18.5, 18.5-24.9, 25-29.9, 30-34.9, 35-39.9, and >40. All reported P values are two-sided; overall a P value < 0.05 was considered significant.Graphs were plotted using GraphPad Prism Version 6.04for Macintosh (GraphPad Software, La Jolla, CA, USA) andcalculations were carried out using IBM SPSS Statistics forMacintosh Version 24.0 (IBM Corp., Armonk, NY, USA).

3. Results

3.1. Increasing Number of Cancelled Transplantations. From2010 to 2016 liver grafts from 2653 donors were offered tothe Charite – Universitatsmedizin Berlin. Organs from 527donors (19.9%) were accepted and successfully transplanted(Figure 1(a)). From the remaining 2126 (80.1%) of offereddonor organs, 1561 (73.4%)were allocated and transplanted at

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Figure 1: Organs offered and accepted 2010-2016. (a) All liver allografts offered to our center, accepted and not accepted. (b) All nonacceptedliver allografts, secondary allocation to another center or discarded from allocation.

other centers and 565 (26.6%) donors could not be allocatedand were not used for transplantation (Figure 1(b)). Of allorgans not used for transplantation, 304 (53.8%) were notprocured at all.

At our center the number of livers accepted and trans-planted significantly decreased (p < 0.001) from 2010 (102,i.e., 32.9%) to 2016 (66, i.e., 10.9%), while the number ofnonaccepted organ offers more than doubled (208 and 536,respectively) in the same time period. Although the numberof patients awaiting OLT at our center decreased from 157 in2010 to 98 in 2016, respectively, there weremore overall offers.

3.2. Reasons for LiverAllograftNonacceptance. Medical issuesof the donors, such as age, biochemical parameters, or steato-sis hepatis, were the primary reason for graft nonacceptance.Steatosis hepatis, as reported by the explant surgeon basedon macroscopic or histopathological assessment of the graft,did not differ significantly from 2010 (15.0%) to 2016 (11.8%),but the number of cancelled liver transplantations due tomacrovesicular steatosis hepatis of the graft significantlyincreased from 2010 to 2016 (p < 0.001) from 15 to 42.

3.3. Donors of Discarded Organs Are Older and Present withHigher Rates of Steatosis Hepatis. In analysis of allocationgroups, i.e., transplanted in our center, allocated elsewhere,or discarded, age differed significantly across groups withdiscarded organs having the highest age (56.0 ± 21.3, p <0.001). In regard to steatosis hepatis, 49.7% of discardedorgans had reports of steatosis hepatis compared to 28.3%transplanted at our center and 27% transplanted elsewhereafter secondary allocation (Figure 2(b)). Age and steatosis

hepatis were significantly associated (p < 0.001); almost halfof donors (45.2%) above the age of 65 had reports of steatosishepatis, compared to 26.5% in donors under the age of 65(Figure 2(a)).

Cause of death due to trauma was the least likely causefor organs to be discarded 12.6% vs. 15.9%, 19.8, respectively, p< 0.001). Furthermore, the laboratory parameters AST, GGT,bilirubin, INR, and creatinine were all significantly higher (p< 0.001) in the group of discarded organs (Table 1).

3.4. Increasing Prevalence of Steatosis Hepatis in AcceptedOrgans. From 2010 to 2016 the proportion of accepted andtransplanted steatotic livers increased significantly (p < 0.001,Figures 3(a) and 3(b)). While 22.3% (n = 22) of liverstransplanted in 2010 had evidence of steatosis hepatis, thisnumber rose to 51.5 % (n = 66) by 2016. During the sametime the proportion of discarded organs which were steatoticsignificantly decreased (p = 0.04) from 61.2% (n = 30) in 2010to 46.8% (n=66) in 2016. In the overall offered donor pool,steatosis hepatis differed in between years (p = 0.007), withan increase of the prevalence from 24.0% in 2013 to 34.7% in2016 (Figure 3(c)).

3.5. Histopathological Reports of Steatosis Hepatis InfluenceAcceptance Rates. Histopathological reports of donors wereavailable in 28.9% (n = 766) of cases. In discarded liver grafts42.5% of organs had a pathology report present compared toonly in 24.7% in transplanted liver grafts. Moderate or severesteatosis hepatis was present in discarded organs in 43.8% (n= 105) of cases with 17.5% (n = 42) of those being severelysteatotic, i.e., ≥ 60% macrovesicular steatosis (Table 2).

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Figure 2: Age and steatosis as influencing factors of acceptance rates. (a) Significantly higher proportion of discarded liver allografts fromsenior donors (39.1%∗∗∗ p < 0.001). (b) Steatosis hepatis is significantly more frequently present in discarded organs (49.7%, ∗∗∗ p < 0.001).

Table 1: Donor data overview.

Total Allocated Transplanted Discarded P valueN 2653 1561 527 565Gender (m) (n, %) 1418 (53.5) 816 (52.3) 268 (51.0) 334 (59.3) 0.007Age1 51.3 ± 20.6 49.0 ± 20.8 53.25 ± 18.2 56.0 ± 21.3 < 0.001Cause of Death < 0.001

Trauma (n, %) 464 (17.5) 309 (19.8) 84 (15.9) 71 (12.6)Cerebrovascular (n, %) 1308 (49.3) 716 (45.9) 288 (54.6) 304 (53.8)Anoxia (n, %) 379 (14.3) 219 (14.0) 74 (14.0) 86 (15.2)Other (n, %) 502 (18.9) 317 (20.3) 81 (15.4) 104 (18.4)

BMI (kg/m2)1 25.5 ± 4.9 25.0 ± 4.3 25.6 ± 4.6 26.8 ± 6.3 < 0.001ICU stay (days)2 3.0 (5) 3 (5) 3 (6) 3 (4) 0.25AST (U/l)2 52.0 (76) 49.0 (71) 47.0 (78) 64.5 (102) < 0.001ALT (U/l)2 34.0 (60) 34.0 (57) 34.0 (59) 36 (70) 0.08GGT (U/l)2 44.0 (93) 39.0 (78) 47.0 (100) 70.0 (161) < 0.001Bilirubin (𝜇mol/l)2 8.7 (10) 8.2 (10) 9.2 (10) 12.0 (14) < 0.001INR2 1.18 (02.4) 1.16 (0.25) 1.19 (0.27) 1.2 (0.29) < 0.001Creatinine (𝜇mol/l)2 70.7 (57.3) 68.0 (55.75) 73.2 (51.85) 79.8 (68.58) < 0.001CRP (mg/l)2 139.9 (162.65) 136.8 (164.75) 142.5 (152.4) 143.6 (175.23) 0.29Na++ (mmol/l)2 148.0 (76.0) 148.0 (11) 147.0 (10) 148.0 (12) 0.15CPR (n, %) 177 (11) 128 (8.2) 14 (2.7) 35 (6.2) < 0.001Steatosis Hepatis insonography or pathology(n, %)

828 (32.1) 409 (27.0) 146 (28.3) 273 (49.7) < 0.001

Steatosis Hepatis confirmedonly in pathology (n, %) 665 (26.6) 334 (22.4) 114 (22.9) 217 (42.4) < 0.0011Data is presented as mean ± standard deviation. 2Data is presented as median (interquartile range). Abbreviations: ALT: alanine-aminotransferase; AST:aspartate-aminotransferase; BMI: body mass index; CPR: cardiopulmonary resuscitation; CRP: C-reactive protein; GGT: gamma-glutamyl transferase; ICU:intensive care unit; INR: international normalized ratio; Na+: serum sodium.

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Figure 3: Steatosis hepatis prelavence and influence on acceptance rates. (a) Declining acceptance rate for all liver allografts during studyperiod (∗ ∗ ∗ p < 0.001). (b) Significant increase in steatosis hepatis in transplantations in our center (∗ ∗ ∗ p < 0.001). (c) Trend in risingsteatosis hepatis prevalence in donor population after 2012.

Table 2: Steatosis hepatis in donors with available histopathological report.

Organs Discarded Transplanted P valuen 240 526No Steatosis Hepatis (n, %) 42 (17.5%) 183 (34.8%)

< 0.001Mild Steatosis (n, %) 93 (38.8%) 274 (52.1%)Moderate Steatosis (n, %) 63 (26.3%) 50 (9.5%)Severe Steatosis (n, %) 42 (17.5%) 19 (3.6%)Data is presented as counts (proportions).

3.6. Steatosis Hepatis Is a Significant Predictor of Liver Nonusein Multivariate Model. A logistic regression was performedto determine the effects of age, BMI, cause of death, history ofsmoking and/or diabetes, blood levels of AST, GGT, bilirubin,INR, creatinine, HCV, HBV, and steatosis hepatis on theprobability of liver grafts being accepted for transplantation.The created model was statistically significant 𝜒2 = 226.25 p< 0.001 and explained 28.0% (Nagelkerke R2) of the variancein organ acceptance while correctly classifying 79.7% of cases(Table 3). Donor age below 50 was a significant predictor oforgan acceptance (p = 0.004, OR = 2.77, 95% CI = 1.29-5.53);ages above 50 were not significantly associated with organacceptance. In cases of normal or overweight donor BMI thiswas equally the case (normalweight: p = 0.001,OR= 7.32, 95%CI = 2.26-3.3; overweight: p = 0.003, OR = 5.6, 95%CI = 1.77-7.73). Compared to donors with positive HCV antibodies, theodds for acceptance were highest in cases of donors beingnegative for HCV antibodies (p < 0.001, OR = 11.79, 95% CI= 4.49-30.93)

Additionally, lack of steatosis hepatis increased odds foracceptance significantly (p < 0.001, OR = 1.88, 95% CI = 1.33-2.65). Relevant biochemical parameters were levels of AST,

GGT, bilirubin, and INR which all presented increased oddsfor organ acceptance with lower values.

A similar logistic regression was performed with allcaseswith available histopathological reports.Thismodelwasstatistically significant 𝜒2(4) = 119.19, p < 0.001 and explained40.2% (Nagelkerke R2) of the variance in organ acceptancewhile correctly classifying 78.8% of cases. Macrovesicularsteatosis of the graft below 5% was associated with higherorgan acceptance (p < 0.001; OR 16.68, 95% CI = 5.01–55.43).In this model only blood levels of creatinine, AST, bilirubin,HCV status, and age were significantly associated with organacceptance.

3.7. Macrovesicular Steatosis Is Predictive for EAD after Trans-plantation. The incidence of EAD significantly increased(p = 0.013) with regard to the degree of macrovesicularsteatosis of the graft. EAD occurred in 13 recipients (21.3%)of grafts with no steatosis, 23 patients (39.0%) that receivedgrafts with mild macrovesicular steatosis, and 9 recipients(56.3%) of grafts with moderate and severe macrovesicularsteatosis (Figure 4(a)). Cold ischemia time greater than 8hours combined with moderate macrovesicular steatosis led

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Table 3: Multivariate logistic regression of organ acceptance.

Organ AcceptanceP value OR (95% CI)

Age (years)< 50 0.004 2.77 (1.29; 5.53)50 – 59 0.372 1.34 (0.68; 2.80)60 – 69 0.172 1.63 (0.81; 3.30)70 – 79 0.567 1.22 (0.62; 2.37)>80 Reference

BMI< 18.5 0.50 1.62 (0.40; 6.52)18.5 – 24.9 0.001 7.32 (2.26; 23.77)25.0 – 29.9 0.003 5.60 (1.77; 17.73)30 – 34.9 0.12 2.56 (0.78; 8.41)35 – 39.9 0.51 1.61 (0.40; 6.55)≥ 40.0 Reference

Cause of DeathTrauma 0.76 1.72 (0.94; 3.14)Cerebrovascular Accident 0.72 1.09 (0.68; 1.73)Anoxia 0.12 1.61 (0.88; 2.94)Other Reference

Smoking (yes) 0.4 1.12 (0.82; 1.67)Diabetes mellitus (yes) 0.88 0.96 (0.59; 1.57)No Steatosis hepatis < 0.001 1.88 (1.33; 2.65)HCV antibody negative < 0.001 11.79 (4.49; 30.93)HBV core antibody negative 0.09 1.62 (0.94; 2.81)AST 0.01 1.0 (1.0; 1.0)GGT < 0.001 1.0 (1.0; 1.0)Bilirubin < 0.001 0.97 (0.96; 0.98)INR 0.04 0.79 (0.62; 0.99)Creatinine 0.47 1.0 (1.0; 1.0)Na+ 0.07 0.98 (0.96; 1.0)CRP 0.76 1.0 (1.0; 1.0)Data is presented as odds ratios (OR) and 95% confidence intervals (CI). Abbreviations: AST: aspartate-aminotransferase; BMI: body mass index; CRP: C-reactive protein; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; INR: international normalized ratio; Na+: serum sodium.

to EAD in 9 (69.2%) cases compared to 28 (30.4%) caseswith cold ischemia time less than 8 hours (p = 0.006). EADled to significantly decreased 1-year recipient (p < 0.001)and graft survival (p < 0.001) (Figure 4(b)). In univariateanalysis, severe macrovesicular steatosis compared to anyother grades of steatosis or no steatosis had a significant effecton 1-year graft survival (p = 0.03; 33.3% vs. 75%) and recipientsurvival (p = 0.04; 33.3% vs 72.0%), while lower degrees ofmacrovesicular steatosis had no effect on graft survival (p =0.13, Figure 4(c)).

4. Discussion

The increasing shortage of suitable organs for transplantationnecessitates constant reevaluation and expansion of organacceptance criteria. The results of our study show a steadyincrease in the overall number of liver graft offers but adecline in the acceptance rate from 2010 to 2016.The increase

in the number of organs offered to our center is in hugediscrepancy with the factual number of organ donationsin the Eurotransplant region and the decreasing number ofrealized liver transplantations. This trend can be explained bymultiple or repeating offers ofmarginal organs fromextendedcriteria donors to different transplant centers and may beattributed to amore restrictive policy for acceptance of organsfrom extended criteria donors for high-MELD patients,which are prioritized in the Eurotransplant allocation system.

Steatosis hepatis is a critical factor for declining anorgan offer. The rising prevalence of steatosis hepatis in thegeneral population is well documented [27, 28]: The overallprevalence today is between 20% and 30% in Europe and 46%in the United States [10, 29]. De Graaf et al. reported a rateof 62% microvesicular and 38% macrovesicular steatosis inliver allografts from deceased donors from 2001 to 2007 inAustralia [16]. Among potential living donors, the prevalenceof biopsy-proven nonalcoholic fatty liver disease ranged from

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Figure 4: Steatosis hepatis prelavence and influence on graft survival. (a) Increased rates of EAD in steatotic liver grafts (p = 0.013). (b)Kaplan-Meier analysis of graft survival of patients with and without early allograft dysfunction (EAD) (p < 0.001). (c) Kaplan-Meier analysisof graft survival in steatotic liver grafts (p = 0.13). S0, no steatosis; S1, mild steatosis; S2, moderate steatosis; S3, severe steatosis. EAD, earlyallograft dysfunction.

15% to 53% in different studies and disqualified 3% to 21% ofpotential liver grafts [10]. In contrast, the extent of steatosison the nonacceptance rate of donated livers is not welldocumented in the literature. Of note, such an evaluationis limited by the fact that there is no standardized protocolfor evaluation of steatosis hepatis of potential liver grafts.The assessment of liver steatosis in potential deceased donorsis usually limited to the sonographic inspection or analysisin computed tomography scans. Histopathological verifica-tion cannot be performed on a routine basis in hospitalsconducting organ retrieval due to logistic reasons. Eventhough, in our cohort, if steatosis hepatis was reported fromultrasound or macroscopic examination, it was confirmed in92.5% of cases with a histopathological analysis, nevertheless,liver grafts are rejected by the transplant center based ona nonstandardized assessment of steatosis hepatis. We hereshow that even though the proportion of steatotic donororgans transplanted in our recipients increased significantlyfrom 2013 to 2016, 42 liver grafts were still rejected due tosteatosis hepatis in 2016, which accounted for a potentialincrease of 63.6% liver transplantations not transplanteddue to steatosis of the graft. Compared to 2010, this rateof not-realized transplantations increased by 49%. Effortsto counteract steatosis hepatis are therefore of immediateclinical relevance and should be therapeutically targeted, e.g.,by conditioning of steatotic liver grafts by machine perfusionduring the preservation period [30].

Our evaluation of reason for nonacceptance confirmsprevious reports from Orman et al. concerning age andBMI [9]. However, the history of diabetes mellitus was notsignificantly associated with organ acceptance in our studycohort.The effect of DCD donors on acceptance could not beinvestigated, as transplantation in Germany is strictly DBDdonors only. Additionally, we could show that a significantly

larger proportion of steatotic organs were discarded andthat prevalence of steatosis hepatis increased over time.In multivariate analysis, we found a significant trend todeclining organs with moderate or severe macrovesicularsteatosis and a positive trend for acceptance of organs withmacrovesicular steatosis hepatis levels below 30%.

Interestingly enough steatosis hepatis coincided withmajor limitations in organ quality such as increased liverinjury parameters and decreased renal function parameters.Donors with steatosis hepatis also had increased ICU stayduration and were older. This combination is challenging,as each factor for itself is known to negatively impactsurvival after liver transplantation [15, 31, 32]. Unlike in theUnited States, recipient survival after liver transplantation hasbeen worse since the introduction of the MELD score [33–35]. Irregularities uncovered in the German liver allocationprogram since 2012 have changed the donor pool and led tofewer suitable donors and reduced overall organ quality [33].Our data on graft acceptance rate reflects this trend and showsa 21.8% drop of acceptance from 2010 to 2016, while organoffer numbers doubled in the same time.

Our evaluation of the outcome of macrovesicular livergrafts confirms previous reports, showing significantly higherrates of EAD compared to grafts with no steatosis. Unlikepreviously reported [16, 23, 36], we observed this effectnot only for severe but also for mild and moderate steatoticgrafts. However, the definition of EAD is not standardized. Aspreviously reported fromWesterkamp et al., the combinationof long CIT and moderate or severe macrovesicular steatosishad detrimental effects on the outcome after transplantation[37]. These effects, which we already observe in grafts withmild steatosis, could demand adapted allocation and preser-vation procedures to reduce CIT and subsequently reduceexpected ischemia-reperfusion injury [18, 19].

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5. Conclusion

In conclusion, our analysis shows a significant decline inliver allograft acceptance rate at our center. In parallel tothe increase of steatosis hepatis in the donor pool there wasa significant increase of steatosis hepatis acceptance at ourcenter especially in cases with histopathological confirmationof less than 30%macrovesicular steatosis. Moreover, we showa strong association of macrovesicular graft steatosis and thedevelopment of EAD, especially in cases with prolonged CIT.Although our results are limited by the retrospective andsingle center analysis, we propose the present data to be atleast relevant for Germany and the Eurotransplant region,where highMELDpatients and organs from extended criteriadonors affect the outcome of liver transplantation. Therapeu-tic concepts are necessary to address the rising prevalenceof steatotic grafts and the inferior outcome associated withtransplantation of such grafts. These concepts should rangefrom limiting the effects of cold ischemia to the graft by exvivo machine perfusion to the metabolic reconditioning ofsteatotic organs prior to transplantation [38].

Abbreviations

ALT: Alanine-aminotransferaseAST: Aspartate-aminotransferaseBMI: Body mass indexCPR: Cardiopulmonary resuscitationCRP: C-reactive proteinDBD: Donation after brain deathDCD: Donation after cardiac deathEAD: Early allograft dysfunctionGGT: Gamma-glutamyl transferaseHCV: Hepatitis C virusHBV: Hepatitis B virusICU: Intensive care unitINR: International normalized ratioIQR: Interquartile rangeOLT: Orthotopic liver transplantationSD: Standard deviationUNOS: United Network for Organ Sharing.

Data Availability

The data used to support the findings of this study areavailable from the corresponding author upon request.

Conflicts of Interest

The authors have no conflicts of interest to disclose regardingthis article.

Acknowledgments

The authors want to thank Jacob de Boer fromEurotransplant, Thomas Mehlitz, Birgit Kulawick, andMichael Hippler-Benscheidt for their assistance in this study.Nathanael Raschzok and Paul Ritschl are participants ofthe BIH Charite Clinician Scientist Program funded by

the Charite – Universitatsmedizin Berlin and the BerlinInstitute of Health. This work was supported by institutionalfunding of the Charite – Universitatsmedizin Berlin. Weacknowledge support from theGermanResearch Foundation(DFG) and the Open Access Publication Fund of Charite –Universitatsmedizin Berlin.

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